Project 3 - Modeling and theory-Abstract One of the greatest challenges for a theory of brain function is the fractured nature of our experimental knowledge about neuronal circuits. The zebrafish larva offers a unique opportunity to mitigate this barrier due to the ability to interrogate whole brain activity at single neuron resolution during ethologically relevant behaviors, the availability of exhaustive genetic tools and the ability to monitor the animal?s behavior over long times. To utilize these benefits the overall project will study a battery of sensorimotor functions in the fish larva, recording its behavioral responses, the brain structures involved, and the neuronal activity at single cell resolution. The primary goal of Project 3 is to integrate findings from the disparate experimental conditions into a coherent quantitative brain wide circuit model, guiding further validation, refinement and hypothesis testing experiments. We will establish a decade long experimental-theoretical-data-processing collaboration, yielding unprecedented advances in our understanding of the functioning of whole brains in animals with complex neuronal structure and function. We will adopt a multiscale approach, summarized as follows: ?Behavioral models - ?capable of an accurate probabilistic prediction of the animal?s actions given its environment and recent behavioral history. ?Conceptual circuit models ?- initial charts identifying the brain structures involved in a given sensorimotor task and their potential projections. ?Functional circuit models ?- systematic quantitative network models, whose functional units are local populations identified through dimensionality reduction of brain wide activity traces. Importantly, this brain wide model will continuously integrate additional structures and circuits as experiments on specific tasks progress. ?Neuronal circuit models ? data from perturbation and EM validation studies at the single neuron/synaptic level will be integrated into single neuron level models for specific local circuits. We will also incorporate data on action selection, multi-sensory integration, and decision making gathered in experiments of Aim 2 of the Overall Project. Model circuits will be integrated into the Multiscale Virtual Fish software platform to allow visualization and interrogation of experimental and modeling data in a common framework. Our multiscale approach will extend to the time domain. To model the brain state dependence of behavioral and neuronal functions (Overall Aim 3) we will build a hierarchical switchable model, with brain state slow dynamics at the top tier, which modulate the lower tier, ongoing fast behavioral and neuronal models (described above). We will seek to extract from our models of the fish brain and behavior general principles likely to generalize across species. This will be tested by using our modeling approach to related experiments in the rat and the fruit fly larva (Project 4), especially in the domain of brain state dynamics and the neuromodulatory control of behavior and sensorimotor processing.